Red cell aggregation is a normal feature of human blood and is elevated in a number of disease states. The purpose of these studies is to develop a better understanding of its contribution to circulatory function in health and disease. In the previous five-year period, we have developed new experimental methods and theoretical models to elucidate the effects of red cell aggregation on flow properties of blood in the venular network. Using the rat spinotrapezius muscle model with Dextran 500 added to the circulating blood to induce red cell aggregation, we have shown that aggregation causes significant blunting of the velocity profile in venules and that flow patterns associated with frequent branching of the venular network limit the development of a cell free layer near the wall. These findings and others provide a mechanistic basis for the hypothesis that red cell aggregation is likely the primary mechanism for he inverse relation between venous vascular resistance and blood flow seen in whole organ studies. We have also obtained new information on random red cell movement in the venular network, which has implications for molecular radial transport in microcirculatory vessels. In the coming grant period we will induce levels of aggregation found in human blood in normal and disease states. We will study the dynamic process of aggregation formation in the venules and the effects of elevated red cell aggregation on this process and on velocity profiles in venules. We will study the effects of red cell aggregation on red cell velocity profiles in arterioles and the relation between the profile and the size and location of aggregates in the flow stream. We will determine the conditions that promote the formation of a cell-free plasma layer at the arteriolar wall. We will also investigate the process of disintegration 01 aggregates in the terminal portion of the arteriolar network and the possibility that at low arterial pressure aggregates lodge in the terminal arterioles and obstruct flow. The random movement of red cells will be measured in the arteriolar network. Mathematical and computational models needed to analyze and interpret the findings from experimental studies will be developed. The findings are expected to improve our understanding of the dynamics 01 red cell aggregation in the microcirculation with relevance for in vivo flow behavior of blood in the human.